System and apparatus for increasing regularity and/or phase-locking of neural activity relating to an epileptic event

ABSTRACT

A method, comprising detecting, in at least a first brain region of a patient, an electrical activity relating to an epileptic activity; determining a first regularity index of said electrical activity; and applying at least one first electrical stimulation to at least one neural target of said patient for treating said epileptic event, in response to said first regularity index being within a first range. A non-transitive, computer-readable storage device for storing instructions that, when executed by a processor, perform the method. A medical device system suitable for use in the method.

This application is a continuation-in-part of U.S. patent applicationSer. No. 13/280,178, entitled “Method, System, and Apparatus forAutomated Termination of a Therapy for an Epileptic Event Upon aDetermination of Effects of a Therapy,” filed Oct. 24, 2011, which is acontinuation-in-part of U.S. patent application Ser. No. 12/729,093,entitled “System and Apparatus for Automated Quantitative Assessment,Optimization and Logging of the Effects of a Therapy,” filed Mar. 22,2010 and currently pending, which claimed priority from co-pending U.S.Provisional Patent Application No. 61/210,850, entitled “System andApparatus for Automated Quantitative Assessment, Optimization andLogging of the Effects of a Therapy,” filed Mar. 23, 2009. U.S. patentapplication Ser. Nos. 13/280,178; 12/729,093; and 61/210,850 are herebyincorporated herein by reference in their entirety.

Safe and effective therapies for pharmaco-resistant seizures are a majorunmet medical need affecting approximately 36% of all epileptics (˜4.1million in the US and ˜18 million worldwide). These subjects have poorquality of life, the large majority are unemployed, suffer fromdepression and are 40 times more likely to die suddenly than age-matchedsubjects in the general population. Brain electrical stimulation, eitherdirectly or indirectly (vagus nerve stimulation), and contingent(triggered by the onset of seizures) or non-contingent (e.g., periodic,round-the-clock), and other therapies such as localized cooling of theepileptogenic zone or direct delivery of drugs to it, hold great promisefor these patients. However, in light of the results of large recentclinical trials showing a modest mean decrease in seizure frequency of40-60% on patients than remain on multiple anti-seizure drugs,optimization is required if they are meet efficaciously andcost-effectively this medical need. This disclosure addresses in anovel, effective, and systematic manner, the complex and demanding taskof optimization of interventional brain therapies for control ofundesirable changes of state. In its preferred embodiment thisdisclosure addresses brain state changes and in particular epilepticseizures. Therapies for other neurological (e.g., pain, movement),psychiatric (e.g., mood; obsessive compulsive), and cardiac (e.g.,arrhythmias) disorders may be optimized using the approaches describedherein.

Epileptic seizures occur with or without discernible or visible clinicalmanifestations. In the case of seizures originating from discrete brainregions (known as partial or “focal” seizures) the electricalabnormalities usually precede the first clinical manifestation(subjective or objective) and in a large number of these patients,impairment or loss of responsiveness occurs some time after the firstclinical manifestation. Also, if the seizure becomes secondarilygeneralized, loss of consciousness (to be distinguished from loss ofresponsiveness) occurs after loss of responsiveness. Commonly, abnormalelectrical activity outlasts the loss of consciousness and consciousnessis regained before responsiveness returns to normal (for the patient)levels. In certain epileptic brains the transition from the non-seizureto the seizure state may be gradual, providing a window for predictionand intervention before the transition is complete. Degree ofresponsiveness may be tested and quantified in real-time using a widevariety of available tests.

Therapy for control of disorders such as epilepsy which manifestintermittently, aperiodically and briefly (ranging from seconds torarely >2 min) and are classified as dynamic, meaning that state changes(from normal to abnormal and vice-versa) are caused by changes in thesystem's control parameter(s) are specially challenging. To increase theprobability of therapeutic success local, global, structural, dynamical,and state factors influencing the state change, must be identified andmeasured with useful precision and at informative time scales. Theseconcepts and considerations required to formulate treatment andoptimization strategies are lacking in the state of the art therapies.

While this disclosure is aimed at optimizing a therapy, nothing in itsspecification precludes delivery of a therapy prior to optimization orwithout optimization. Indeed, optimization cannot take place if atherapy has not been administered and its effects (beneficial anddetrimental) quantified. If a therapy cannot be optimized (in terms ofincreasing its beneficial effects), optimization may be effected bydecreasing the number or intensity and duration of its adverse events.Adverse effects include, but are not limited to, increase in seizurefrequency or severity, cognitive impairment in functions such as memory,language, mood (depression or mania), and/or psychosis. These adverseeffects may be quantified using cognitive, electrical, thermal, opticaland other signals and logged to computer memory. In the case of signalsthat lack easily detectable or recognizable electrical or othercorrelates, they may be characterized using a semi-quantitative approachsuch as psychiatric scales, care-giver observations or patient diaries.

The term “therapy” may be interchangeably used with the term control forwhich a theory exists (Control Theory) in the field of engineering.Since therapy and control share the same aim, it is appropriate to adoptcertain concepts form this theory as well as from the fields of dynamicsto generate a rational approach and strategy for the management ofpharmaco-resistant seizures.

The epileptic brain may be conceptualized as a non-stationary,non-linear, “noisy” system that undergoes sudden unexplained reversibletransitions from the non-seizure state. The manner in which thistransition occurs may be “gradual” (through a process of “attractordeformation”) or sudden (through a “leap” from one state to another) asobserved in bi-stable or multi-stable systems. Dynamical theory teachesthat a system may be defined by its dimension (which corresponds to theminimum number of variables required to specify it). The identificationof a system's dimension greatly benefits from the identification of aspatio-temporal scale of observation that corresponds to arepresentative sample of the system (so-called mesoscopic scale), thusobviating the need to study the whole system at all scales, a dauntingand impracticable task in the case of the mammalian brain. The epilepticbrain's dimensionality and its mesoscopic scale have not beeneffectively specified to date. This knowledge void forces the treatmentof the brain as a “black-box”.

While by definition a “black-box” is not amenable to direct inquiry, itcan be indirectly studied through perturbations of system inputs. Aknown, well characterized input is “fed” into the “black-box” and theoutput is carefully recorded and characterized quantitatively orqualitatively and compared to the input. Transformations, if any to theinput properties provide indirect but useful information about the“black-box” that may be captured mathematically as transfer functions.For example, if doubling the amplitude of the input translates intodoubling of the output, the system is considered linear. However ifdoubling the input causes an exponential increase in the output, thesystem is non-linear (likely the brain's case). If sine waves are fedinto the black box and 60 Hz activity appears on them as they exit thebox, it is reasonable to infer that the box corrupts the waves and is“noisy”. Successful control of the behavior of “black-boxes” cannotoccur if the measurements of its output are not representative of thestate(s) and site(s) from where they are obtained, reasonably preciseand also reproducible from measurement to measurement.

Global and local factors (many state-dependent) also shape the responseto therapies. For example, the rate and direction of diffusion ofparticles and molecules in animal tissue (e.g. brain), depends onmultiple factors including size, chemical valence and the size andtortuosity of the extracellular space. In certain tissues, such as thebrain's, the average values of the dielectric constant, or permittivity,and of the resistance are not equal at all points of the volume whichthe particles and molecules occupy. This anisotropy, which varies by afactor of 5-10 between two orthogonally-selected directions, such asbetween the vertical (or radial) and horizontal (or transverse)directions in a brain's cortex or its axons, ensures that diffusion ofendogenous and exogenous (e.g., electrical stimulation) currents is nothomogenous. This lack of homogeneity (and of isotropy) in the case of atherapy (e.g., electrical stimulation) that must diffuse through thetissue to exert its beneficial action is likely to decrease efficacy, afeature that must be considered for control and optimization purposes.

The diffusions of electrical currents within the brain, which as vectorshave both magnitude (potential) and direction, are the result ofelectrostatic forces caused by the transient accumulation of charges andalso of electrodynamic actions arising from ionic or electronic currentsin the volume which surrounds the local accumulations of such charges.Intracortical diffusion of electrical charges (ions) and currents, takesplace at several spatial domains or scales (active membrane sites,cells, columns and the cortical synergic groups where they flowdifferentially through the lattice of intercellular spaces and throughthe network of glial cells. These flows occur through a large number ofroutes at their disposal, each route being the path for only a smallpart of the total current (Kirchhoff's law), a “fractionation” that mayresult in insufficient (or excessive) current densities and low or noefficacy or adverse effects in certain sites.

An additional challenge to controlling brain state changes is thattissue anisotropy is not uniform or constant but it varies as a functionof differences in cortical cytoarchitecture and of the state ofactivation within the volume where putative (endogenous) or exogenous(e.g., electrical stimulation) currents diffuse. These inter-regional orareal differences translate into time- and space-constant differencesthat make the probability of generation of action potentials and theirconduction velocities behave differentially. When present, thesedifferences lead to the spatio-temporal dispersion of endogenous orexogenous (e.g., electrical stimulation) currents and to a lower thandesirable current flux through the region of interest—and thuspotentially to loss of therapeutic efficacy. However, the opposite mayalso occur and current flux may be higher than desirable for efficaciouscontrol or safety purposes. The fact that electrical currents bothtrigger and control seizures depending on the stimulation parametersused, such as frequency and intensity, among many other factors, shouldnot be ignored by those who use this modality for therapeutic purposes.In addition to the inherent widespread morphological or structuralanisotropy of nervous tissue, diffusion of electrical potentials alsodepend on: a) the state (at both global and local levels and at long andshort time scales) of the network; b) on the level (spike frequency) andpattern of spike activity and the “valence” (inhibitory or excitatory)of inputs and outputs, which are likely reflected in changes in tissueconductivity/diffusivity and responsivity to both endogenous andexogenous currents. For example, tissue resistivity is altered by burstsof epileptiform discharges of only a few seconds duration and frequentseizures often alter tissue osmolality, both of which are likely tonegatively impact therapeutic efficacy, unless these factors are takeninto account and measured.

As for electrical stimulation, the most investigated therapeuticmodality for pharmaco-resistant epilepsies, the electric field E_(i) atevery point i on the surface of a charged needle (which closelyapproximates in shape the electrodes used in humans for treatmentpurposes) is similar to the set of diffusion limited aggregation growthprobabilities and in this sense, the electric field E_(i) is also amulti-fractal set. This means that different “regions” in the electricfield (and by extension in the tissue where the field is active) are notonly fractal but have different fractal values or properties atdifferent points. That an electric field as described above is amulti-fractal set brings to the fore one of the central themes of thiswork, the spatio-temporal “inhomogeneity” of a therapy (electrical) andthe requirement (for optimization of this treatment modality) to applyconcepts (from multi-fractal theory, among others) to quantitativelycharacterize this complex phenomenon.

Prior art therapies also ignore the dampening and the linear andnon-linear distortions of frequency, phase, harmonics and amplitude thatinvariably occur as currents travel through brain tissue. Morespecifically, prior art therapies and interventions for blocking,abating, or preventing undesirable state changes ignore tissueanisotropy, dielectric hysteresis, state and circadian influences atlocal and global scales and the changing nature (non-stationarity) inthe type, pattern and level of neuronal activity as a function of stateand time as reflected in intra-individual and inter-individualdifferences in seizures.

The present inventor has investigated the foregoing issues in conductingresearch to improve therapies available to epileptic patients. Figurespresented in U.S. patent application Ser. No. 12/729,093 and 61/210,850depict the power spectrum (a representative estimation of brainactivity) of neuronal activity recorded over 162 hours from the samesite in the same human subjects. Those figures demonstrate how theactivity of the epileptogenic zone as reflected in the power spectrumchanges as a function of time. A look at those spectrograms and at thetemporal evolution of the values of the decimal logarithm of thestandard deviation; of the generalized Hurst exponent; and of thesingularity spectra width values of two seizures recorded from 11subjects (each subject's seizures are in the same row), point clearly tothe importance of tailoring therapy to intra- and inter-individualdifferences; it is improbable that electrical stimulation with fixedparameters (the current state-of the-art) delivered to each of theseseizures will have the same effect, let alone that it will be uniformlybeneficial.

The inhomogeneity/lacunarity of involvement of tissue during anundesirable event, as seen in figures presented in U.S. patentapplication Ser. No. 12/729,093 and 61/210,850, underscores theimportance of quantifying and accounting for lack of uniform tissueinvolvement (inhomogeneity) by these abnormal events.

If seizure properties features are determined using spectral methods andclassified into clusters (each cluster represents a given type ofseizure) using vectors of their properties (e.g., the log of thestandard deviation, the singularity spectra width values, etc.), theinventor has found that there is more than one cluster or seizure typefor each subject, for seizures originating from the same site, and thatthe number of clusters changes in time, suggesting corresponding changesin the number of main “modes” of neural activity. The non-stationarityof seizures origin in a subject from the same brain regions is supportedby recent the observation that signal spectral and other propertieschange throughout a seizure, a phenomenon that draws attention to thelimitations (e.g., lower efficacy, more adverse events) of using thesame therapy (e.g, constant parameters) throughout the course of aseizure and of not tailoring it to its spectral properties, complexity,entropy or information measures. The non-stationarity of seizures(largest around onset and termination) may reflect “start-up transients”(in a dynamical sense) and temporo-spatial dispersion of the ictalsignal (which impacts the signal-to-noise ratio). These and local andglobal state-dependencies of certain signal features, account in partfor within-seizure spectral and other fluctuations or non-stationarybehavior.

Seizures may have a latent circadian periodicity which could beextracted as periodicity in the variation of the pseudo-F-statisticmaximum values. This periodicity may disappear as a function of time,state and other factors. A figure presented in U.S. patent applicationSer. No. 12/729,093 and 61/210,850 depicts the time evolution of thevalues of the Pseudo-F statistic (a measure of cluster tightness) ofseizures recorded from the same site and from the same individual.Notice the red clouds seen at 1.2 (˜12 hr) and 1.4 (˜24 hr) in a log oftime axis) and present from the start of the recording and indicative ofa circadian tendency for seizure properties to cluster, that is, to behighly similar, vanishes after approximately 110 hours, indicating theloss of the circadian trend. This observation further exposes thevariability of abnormal brain activity over intermediate time scales(tens of hours), variability that must be detected and measured tooptimize (as a function of time) therapeutic efficacy.

Other important factors that are ignored by current therapies are: (i)seizure blockage does not necessarily translate into prevention of lossof cognitive functions, the most disabling seizure symptom; (ii) theinherent and inevitable delay (vide supra) in arrival of the therapy toits target site, delay which depends among others on the therapeuticmodality (relatively short for electrical currents and relatively longfor drugs and thermal energy); (iii) the degree (low or high) ofmorphological similarity among oscillations that make up a seizure,determines the probability (high if the oscillations are highly similar)of blockage especially if electrical stimulation is the therapy ofchoice; (iv) the lack of uniformity in flow direction and in density ofboth the abnormal activity and the therapy, as well the differences intheir speeds of propagation, their phase-locking levels, and theirdegrees of regularity.

SUMMARY OF THE DISCLOSURE

In one embodiment, the present disclosure provides a method, comprising:detecting, in at least a first brain region of a patient, an electricalactivity relating to an epileptic activity; determining a firstregularity index of said electrical activity; and applying at least onefirst electrical stimulation to at least one neural target of saidpatient for treating said epileptic event, in response to said firstregularity index being within a first range.

In one embodiment, the present disclosure provides a method, comprising:detecting a first electrical activity relating to a first epilepticactivity in at least a first brain sub-region of a patient; detecting asecond electrical activity relating to a second epileptic activity in atleast a second brain sub-region of said patient; determining aphase-locking index between said first electrical activity and saidsecond electrical activity; and applying at least one first electricalstimulation to at least one neural target of said patient for treatingsaid epileptic activity, in response to said phase-locking index beinginside a first range.

In one embodiment, the present disclosure provides a method, comprising:detecting a first electrical activity relating to a first epilepticactivity in at least a first brain sub-region of a patient; detecting asecond electrical activity relating to a second epileptic activity in atleast a second brain sub-region of said patient; determining aphase-locking index between at least said first electrical activity andsaid second electrical activity; applying at least one first electricalstimulation to at least one neural target of said patient to modify saidphase-locking index if said phase-locking index is outside a firstrange; and applying at least one second electrical stimulation to atleast one neural target of said patient to treat said epilepticactivity.

In one embodiment, the present disclosure provides a medical devicesystem, comprising: an epileptic event detection module configured todetect an epileptic event; at least one sensor configured to collect oneor more electrical activity signals from at least one region of thebrain of a patient; a regularization determination module configured todetermine the regularity of said electrical activity; a neuronalregularization module configured to modify a regularity index ofelectrical activity in said at least one brain region of said patient; aphase-locking determination module configured to determine the degree ofphase-locking between said first electrical activity and said secondelectrical activity; a phase-locking module configured to modify aphase-locking index between a first electrical activity in said at leastone brain region and a second electrical activity in a second brainregion of said patient; and a stimulation module configured to apply anelectrical stimulation to at least one neural target of said patientbased on an indication of said epileptic event.

In one embodiment, the present disclosure provides a non-transitive,computer-readable storage device for storing instructions that, whenexecuted by a processor, perform a method as described herein.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1A depicts a medical device system, comprising an electrodeimplanted in the brain of a patient, in accordance with one illustrativeembodiment of the present disclosure.

FIG. 1B depicts a medical device system, comprising a plurality ofelectrodes implanted in the brain or coupled to a cranial nerve of apatient, in accordance with one illustrative embodiment of the presentdisclosure.

FIG. 2 presents a block diagram of a medical device system, inaccordance with one illustrative embodiment of the present disclosure.

FIG. 3 presents a block diagram of an electrical activity zone unit, inaccordance with one illustrative embodiment of the present disclosure.

FIG. 4 depicts an exemplary mapping of a patient's brain activity, inaccordance with one illustrative embodiment of the present disclosure.

FIG. 5 depicts a sensor/electrode system, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 6 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 7 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 8 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 9 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 10( a) shows electrical measurements of epileptic brain activityand the response to neurostimulation for six different seizures.

FIG. 10( b) shows electrical measurements of epileptic brain activityand the response to neurostimulation for two different seizures.

FIG. 10( c) shows an enlarged view of a portion of the response evokedby electrical pulses applied to Seizure Number 6 in FIG. 10( a).

FIG. 11 shows a representative evolution of electrical activity relatingto a patient's epileptic event from less regular to more regular.

FIG. 12A shows examples of oscillations recorded from various sites thathave different (high and very low) regularity index values.

FIG. 12B shows examples of neuronal oscillations that are phase-lockedbut not phase aligned (1 and 2) and of oscillations that are both phasealigned and locked (2 and 3)

FIG. 13 depicts a neural region (C) and two sub-regions (A and B), eachgenerating highly regular oscillations but at different frequencies.

FIG. 14 depicts infra-slow rhythms of brain electrical activity.

DETAILED DESCRIPTION OF THE DISCLOSURE

The occurrence of trains of oscillations with highly similar waveforms(frequency and amplitude) within a brain region/network or between brainregions/networks may be interpreted as an indication that theseoscillations are generated by highly regular and/or phase-lockedgenerators. More detail regarding these topics can be found in U.S.patent application Ser. No. 12/729,093, incorporated herein byreference.

Embodiments of the present disclosure provide for a method, system, andapparatus for determining a regularity of neuronal activities in one ormore areas of a patient's brain. The neuronal activity may relate to anepileptic event. In one embodiment of this disclosure said neuronalactivity is electrical. In other embodiments, the neuronal activity maybe chemical, metabolic, or mechanical. Based upon the degree ofregularity, a stimulation signal, e.g., a pulse signal, may be appliedto control or reduce the abnormal or undesirable electrical activity.Alternatively or in addition, the degree of regularity may be modifiedby a stimulation signal provided by a device.

“Regularity” refers herein to self-similarity between two or moreoccurrences of a cyclic phenomenon (e.g., brain or neuronaloscillations, for example, electrical oscillations). A quantifiedmeasure of regularity may be termed a “regularity index.”

In one embodiment, a phase-locking index that relates to the degree ofphase-locking of electrical activities corresponding to two or morebrain regions or within a brain region may be determined. Based upon thephase-locking index, a stimulation signal is provided to reduce or blockthe abnormal electrical activity. The parameters of said electricalsignal may be selected based on the level of neuronal regularity and/orphase-locking within or between regions in reference to the level ofregularity and/or phase-locking that characterizes the non-seizure stateoscillations. Specifically, if the regularity and/or phase-locking indexdrops during a seizure in reference to the non-seizure value of theindex, parameters that increase said seizure regularity and/orphase-locking level may be applied to the region generating the seizure;if the regularity and/or phase-locking index increases during a seizurerelative to the non-seizure value of the index, electrical signals withparameters that decrease regularity and/or phase-locking may be applied.

Turning now to FIG. 1A, a stylized medical device system is depicted.The medical device system comprises a medical device 200 and at leastone sensor 212.

In some embodiments, the medical device 200 may be implantable, while inother embodiments, such as that shown in FIG. 1B, the medical device 200may be completely external to the body of the patient.

The sensor 212 may be implanted in the patient's body, worn external tothe patient's body, or positioned in proximity to but not in contactwith the patient's body. The sensor 212 may be configured to receiveneurologic, autonomic, endocrine, metabolic, tissue stress marker,physical fitness/body integrity data or other data from the patient'sbody.

FIG. 1A depicts a medical device system comprising a medical device 200being in wireless communication 211 with the at least one sensor 212. Inother embodiments (not shown), the medical device 200 may be incommunication with the at least one sensor 212 via a lead or other wiredcommunication channel.

The medical device system shown in FIG. 1A also includes at least oneneuronal regularization electrode 283. In the depicted embodiment, theneuronal regularization electrode 283 may be implanted in the patient'sbrain 105 such that the terminus of the electrode 283 may be inproximity to a brain region 110 which may be an epileptogenic focus(depicted by a star) of the patient. The neuronal regularizationelectrode 283 may be used for delivery of an electrical stimulation toincrease a degree of regularity of electrical activity in the brainregion 110.

Not shown in FIG. 1A is an alternative embodiment, wherein a pluralityof neuronal regularization electrodes 283 may be implanted in thepatient's brain 105. A plurality of neuronal regularization electrodes283 may be implanted such that their termini may all be in proximity toa single brain region. Alternatively, the plurality of neuronalregularization electrodes 283 may be implanted such that their terminiare in proximity to a plurality of brain regions. For example, if thepatient has multiple epileptogenic “foci”, a plurality of neuronalregularization electrodes 283 may be implanted such that eachepileptogenic focus may have at least one neuronal regularizationelectrodes terminus in proximity thereto. Electrodes may be alsoimplanted in brain regions that are not epileptogenic but that may bedirectly or indirectly connected to the epileptogenic regions.

Also, FIG. 1A depicts the medical device 200 being in wirelesscommunication 281 with the at least one neuronal regularizationelectrodes 283. In other embodiments (not shown), the medical device 200may be in communication with the at least one neuronal regularizationelectrodes 283 via a lead or other wired communication channel.

FIG. 1B depicts an alternative embodiment of a medical device systemcomprising a medical device 200. The sensor 212 and its communicationwith the medical device 200 have been described above with reference toFIG. 1A. Similarly, the at least one neuronal regularization electrode283 and its communication with the medical device 200 have beendescribed above with reference to FIG. 1A. In FIG. 1B, the depictedcommunication between the medical device 200 and the neuronalregularization electrode 283 is represented by a wireless communication281 a. In the embodiment depicted in FIG. 1B, the brain region which maybe an epileptogenic focus (depicted by a star) of the patient isidentified as brain region 110 a.

FIG. 1B additionally depicts the medical device system as comprising anelectrode 282. In the depicted embodiment, the electrode 282 may beimplanted in the patient's brain 105 such that the terminus of theelectrode 282 may be in proximity to a brain region 110 b (depicted byan octagon) of the patient. The brain region 110 b may be anepileptogenic focus, or it may be not an epileptogenic focus. Theelectrode 282 may be used for delivery of an electrical stimulation toincrease a degree of regularity of electrical activity in the brainregion 110 b or of regions connected to it. Alternatively or inaddition, the electrode 282 may be used for delivery of an electricaltherapy for an epileptic event. Even if the brain region 110 b is not anepileptogenic focus, delivery of an electrical stimulation therapy tobrain region 110 b may be efficacious against the epileptic event.

Similarly to neuronal regularization electrode(s) 283, the medicaldevice system may comprise a plurality of electrodes 282 (not shown).

In other embodiments, not shown in FIG. 1B, a single (set of)electrode(s) 282 may be used for neuronal regularization and thedelivery of therapy.

FIG. 1B also depicts the patient's vagus nerve 106, to whichelectrode(s) 284 is affixed. Electrode(s) 284 is shown in communicationwith the medical device 200 via lead 281 c. Electrode(s) 284 may be usedto gather signals useful in detecting an epileptic event, regularizingthe activity of an epileptic event or treating an epileptic event.

FIG. 1B depicts the medical device 200 being in wired communication(e.g., a lead) 281 b with the at least one electrode 282. In otherembodiments (not shown), the medical device 200 may be in wirelesscommunication with the at least one electrode 282.

In various embodiments, electrode(s) 282, 283, and/or 284 may eachperform one or more of gathering signals useful in detecting anepileptic event, regularizing electrical activity relating to anepileptic event, or treating an epileptic event. An electrode 282-284may comprise one or more contacts, and each contact may independentlyperform one or more of gathering signals useful in detecting anepileptic event, regularizing electrical activity relating to anepileptic event, or treating an epileptic event.

FIG. 2 presents a block diagram of a medical device system, inaccordance with one illustrative embodiment of the present disclosure.

The medical device 200 may comprise a controller 210 capable ofcontrolling various aspects of the operation of the medical device 200.The controller 210 may be capable of receiving internal data or externaldata, and in one embodiment, may be capable of causing a stimulationmodule 275 to generate and deliver an electrical signal to targettissues of the patient's body for treating a medical condition. Forexample, the controller 210 may receive manual instructions from anoperator externally, or may cause the electrical stimulation signal tobe generated and delivered based on internal calculations andprogramming. The controller 210 may be capable of affectingsubstantially all functions of the medical device 200.

The controller 210 may comprise various components, such as a processor215, a memory 217, etc. The processor 215 may comprise one or moremicrocontrollers, microprocessors, etc., capable of performing variousexecutions of software components. The memory 217 may comprise variousmemory portions where a number of types of data (e.g., internal data,external data instructions, software codes, status data, diagnosticdata, etc.) may be stored. The memory 217 may comprise one or more ofrandom access memory (RAM), dynamic random access memory (DRAM),electrically erasable programmable read-only memory (EEPROM), flashmemory, etc.

In other embodiments, one or more electrode(s) 282 may be adapted to bepositioned in at least one neural target of a patient. The neural targetmay be one or more of a target area of the brain region of the patient,a target area of a cranial nerve of a patient (such as a target area ofa vagus nerve of a patient), a target area of the spinal cord of apatient, a target area of a sympathetic nerve structure of the patient,a target area of a peripheral nerve of the patient, a target area of anerve root of a patient, or a target area of skin receptors of apatient.

The medical device 200 may also comprise a power supply 230. The powersupply 230 may comprise a battery, voltage regulators, capacitors, etc.,to provide power for the operation of the medical device 200, includingdelivering a therapeutic electrical signal. The power supply 230comprises a power source that in some embodiments may be rechargeable.In other embodiments, a non-rechargeable power source may be used. Thepower supply 230 provides power for the operation of the medical device200, including electronic operations and the electrical signalgeneration and delivery functions. The power supply 230 may comprise alithium/thionyl chloride cell or a lithium/carbon monofluoride (LiCFx)cell if the medical device 200 is implantable, or may compriseconventional watch or 9V batteries for external (i.e., non-implantable)embodiments. Other battery types known in the art of medical devices mayalso be used.

The medical device 200 may also comprise a communication unit 260capable of facilitating communications between the medical device 200and various devices. In particular, the communication unit 260 may becapable of providing transmission and reception of electronic signals toand from a monitoring unit 270, such as a handheld computer or PDA thatcan communicate with the medical device 200 wirelessly or by cable. Thecommunication unit 260 may include hardware, software, firmware, or anycombination thereof.

The medical device 200 may also comprise one or more sensor(s) 212coupled via sensor lead(s) 211 to the medical device 200. Sensor(s) 212are capable of collecting one or more body signals from a patient'sbody. Exemplary body signals include, but are not limited to, thoserelated to autonomic activity, such as the patient's heart beat, bloodpressure, and/or temperature, among others; signals related to aneurologic activity, signals related to a metabolic activity, signalsrelated to an endocrine activity, and signals related to tissue stressmarkers.

In one embodiment, the sensor(s) 212 may collect electrical datarelating to electrical activity from one or more regions or subregionsof the human brain. The electrical activity may relate to an epilepticevent in the region(s) or subregion(s). As used herein, any two or morebrain region(s) and/or sub-region(s) may be physically contiguous,physically adjacent, physically non-adjacent, anatomically connected,electrically connected, or two or more thereof.

Sensor(s) 212 may be unimodal or multimodal (e.g., collect one or moreof electrical, optical, chemical, pressure, thermal, acoustic, etc.signals). Their number, location, functions, and status (active ordormant) may vary according to the task at hand.

Whatever the signal type collected by the sensor(s) 212, the signal(s)may be filtered or processed prior to further use by other modules ofthe medical device 200, or raw signals may be used by other modules. Inone embodiment, the sensor(s) 212 may be the same as electrode(s) 282,283, and/or 284. In other embodiments, the sensor(s) 212 are separatefrom electrode(s) 282, 283, and/or 284; for example, the sensor(s) 212may be placed on the patient's skin, such as over the patient's heart orelsewhere on the patient's torso. The sensor(s) 212 and accompanyingleads may be considered an interface for the medical device 200 toreceive at least one of autonomic data, neurologic data, metabolic data,endocrine data, stress marker data, quality of life data, physicalfitness/body integrity or other data.

More information on body signals, such as cardiac signals, respiratorysignals, body movement signals, skin resistance signals, responsivenesssignals, and awareness signals, as well as techniques and devices forthe acquisition thereof and the determination of autonomic indices,neurologic indices, metabolic indices, endocrine indices, and stressmarker indices, is provided by U.S. patent application Ser. No.12/896,525, filed Oct. 1, 2010, which is incorporated herein byreference in its entirety.

The medical device may also comprise an epileptic event detection module265. The epileptic event detection module 265 may be configured todetect an epileptic event from any desired input suitable for doing so.For example, in one embodiment, the epileptic event detection module 265may be configured to detect an epileptic event from brain electricalactivity data, e.g., EEG data. In another exemplary embodiment, theepileptic event detection module 265 may be configured to detect anepileptic event based on the signal(s) from elsewhere (e.g.,extra-cerebral) in the patient's body. These signals may, but need not,be provided by sensor(s) 212. In one particular embodiment, theepileptic event detection module 265 may be configured to detect anepileptic event based on at least one of a cardiac activity indicativeof an epileptic event or a motor activity indicative of an epilepticevent.

The term extra-cerebral signal(s), as used herein, denotes signals thatmay or may not originate from the brain but that do not require sensorsor electrodes place on the head, or on/in the brain, to record them.Examples of extracerebral signals include but are not limited tocardiac, metabolic, etc. Certain neurologic signals such as kinetic orcognitive (reaction time, memory scores, etc.) are consideredextra-cerebral (even though they originate in the brain) because theyare recordable outside the head or brain, unlike EEG or ECoG as recordedwith state-of the-art equipment and methods.

Epileptic events are likely to exhibit regular neuronal activity. In oneembodiment, an epileptic event may be detected by determining the degreeof regularity of electrical activity in a first brain region of thepatient.

More information regarding detection of epileptic events from sensedbody signals, and determination of severity of and body locationsaffected by epileptic events, can be found in U.S. patent applicationSer. No. 12/756,065, filed Apr. 7, 2010; U.S. patent application Ser.No. 12/770,562, filed Apr. 29, 2010; U.S. patent application Ser. No.12/896,525, filed Oct. 1, 2010; U.S. patent application Ser. No.13/040,996, filed Mar. 4, 2011; U.S. patent application Ser. No.13/091,033, filed Apr. 20, 2011; and U.S. patent application Ser. No.13/098,262, filed Apr. 29, 2011; all of which are hereby incorporatedherein by reference in their entirety.

The medical device 200 may also comprise a regularity determinationmodule 266. The regularity determination module 266 may be configured todetermine the level(s) of regularity within one or more regions orsubregions of the patient's brain. The regularity determination module266 may do so by using any available data, such as data extracted fromsignals gathered by sensor(s) 212, and calculating one or more of ameasure of amplitude variance, a measure of frequency variance, ameasure of zero-crossings interval variance, a measure of ascending anddescending slope variances, a number of extrema, a polarity of extrema,a box count, a polynomial fitting to measure the error of polynomialapproximation, a Lipschitz exponent of one of the foregoing, or a Holderexponent of one of the foregoing. From the calculation, the regularitydetermination module 266 may determine whether the degree of regularityis within a first range, such as a range suggestive that the epilepticevent would be amenable to treatment as described below.

The regularity of neuronal oscillations may be determined from anautocorrelation function, a template-matching function (wherein a firstoccurrence of the cyclic phenomenon provides the template for matchinglater occurrences thereof), or the variance of amplitude, frequency,zero-crossing interval, extrema, slope, or other parameters between thetwo or more occurrences of the cyclic phenomenon, among others.Determining regularity from the variance of one or more parameters maybe computationally more efficient, which may be desirable to preservebattery life, expedite calculation, or both. Fractal/multifractal toolsmay be also applied to the body signal(s) to determine their degree ofregularity of their oscillations.

In one embodiment, a regularity index may be determined relativelyrapidly, such as from signals collected during a window comprising fromtwo to twenty wavelengths of a predominant oscillation of the electricalactivity. Typical predominant oscillations of epileptic electricalactivity have a frequency from about 8-45 Hz, from which a regularityindex according to this embodiment may be determined on signalscollected over from about 20 msec to 2.5 sec.

As stated elsewhere, the regularity index may be calculated based on araw signal of the electrical activity, or on a filtered or otherwiseprocessed signal. A filter may be selected such that the regularityindex may be determined at least in part on a frequency component of theelectrical activity. The frequency component may be a single frequencyor a frequency band. For example, the frequency component may have afrequency or band in the range of 1-6 Hz, 8-45 Hz, 1-200 Hz, DC to 100Hz, 100-1000 Hz, or DC to 1000 Hz.

In one embodiment, the regularity index may be determined based on apower spectral density of the electrical activity or a power level of aselected frequency component. For example, the frequency componenthaving the highest power level may be selected such that the regularityindex may be determined at least in part on it. In another embodiment,the regularity index may be determined based on a selected frequencycomponent, independent of its power level. For example, a particularfrequency or band may be known to be generally implicated in electricalactivity relating to the patient's stereotypical epileptic events.

A regularity index of the electrical activity may comprise informationrelating to the oscillation morphology, amplitude, and frequency of theelectrical activity.

The concept of regularity may be illuminated in qualitative terms byconsideration of FIG. 10( a). This figure shows the effect of fivecathodal monophasic (DC) pulses on six different seizures, recorded fromthe same site.

Prior to the application of the stimulation at time 0, the regularity ofthe electrical activity of seizures 1, 2, 5, and 6 is apparent.Contrariwise, the lack of regularity of the electrical activity ofseizures 3 and 4 is also apparent.

FIG. 10( a) also shows quantification of regularity. A regularity indexwas calculated by use of an autocorrelation function frompre-stimulation data relating to all seizures. Seizures 1, 2, 5, and 6had regularity indices from 0.72-0.91, whereas seizures 3-4 hadregularity indices from 0.12-0.28.

FIGS. 10( a) and 10 (b) show a practical benefit of increasing theregularity of electrical activity in at least one brain region of apatient. Seizures 1, 2, 5, and 6, characterized by high regularity, wereattenuated/blocked by electrical stimulation therapy. Seizures 3-4,characterized by low regularity, were not attenuated/blocked byelectrical stimulation therapy. It should be noted that even a singlecathodal monophasic pulse may abolish a highly regular seizure, whilehaving no effect on one with low regularity.

FIG. 10( c) further illuminates the points raised above. This figureshows the impulse or evoked response to monophasic cathodal stimulationof one of the seizures shown in FIG. 10( a). The impulse responses tocathodal stimulations show subtle phase shifts (phase resetting) whichare predictive of a beneficial or non-beneficial response. Usingavailable optimization search methods, the timing of delivery of asingle (or very pulses) to cause the desirable (beneficial) phase may befound for each seizure.

The medical device 200 may also comprise a regularity modificationmodule 267. The regularity modification module 267 may be configured todeliver a neuronal regularization electrical signal to a brain region ofa patient through electrode(s) 282, 283, and or 284.

The delivery of a neuronal regularization electrical signal by theregularity modification module 267 may be based on a finding by theregularity determination module 266 that the degree of regularity of theelectrical activity in question is outside a first range, such as at alow level, suggestive that the epileptic event would not be amenable totreatment as described below.

Similarly to the regularity determination module 266 and regularitymodification module 267 described above, the medical device 200 may alsocomprise a phase-locking determination module 268 and a phase-lockingmodification module 269. The phase-locking determination module 268 maydetermine a degree of phase-locking of electrical activity between tworegions and/or subregions of the patient's brain, and the phase-lockingmodification module 269 may modify the degree of phase-locking to renderthe epileptic event more amenable to treatment as described below. Thephase-locking modification module 269 may modify the degree ofphase-locking by delivering an electrical stimulation to a neural targetvia one or more electrodes 282, 283, or 284.

The electrodes 282 may be configured for modifying (e.g., increasing ordecreasing) the phase-locking level between subregions within a regionor between brain regions of a patient, such as two neural targets.Electrodes suitable for this application are described in U.S. patentapplication Ser. No. 11/151,386, which is hereby incorporated herein byreference.

As stated above, in one embodiment, the medical device 200 may alsocomprise a stimulation module 275 capable of generating and deliveringan electrical therapy delivered to one or more electrodes 282.

Therapy may be delivered to the electrode(s) 282 by the stimulationmodule 275 based upon instructions from the controller 210. Thestimulation module 275 may comprise various circuitry, such aselectrical signal generators, impedance control circuitry to control theimpedance “seen” by the leads, and other circuitry that receivesinstructions relating to the delivery of the electrical signal totissue. The stimulation module 275 may be capable of deliveringelectrical therapy over leads to the electrode(s) 282. The stimulationmodule 275 may be configured to apply an electrical therapy, which maycomprise one or more stimulation pulses, to at least one neural targetof the patient based on an indication of an epileptic event.

The electrical therapy, and/or each stimulation pulse thereof, maycomprise a plurality of parameters, such as waveform, pulse width,number of pulses, inter-pulse interval, amplitude, or phase/polarity,the timing of pulse delivery in reference to the time a zero-crossingoccurs, the timing of pulse delivery in reference to the time anextremum occurs, or the timing of pulse delivery in reference to aregion of an ascending or descending slope of a neuronal oscillation,among others. In one embodiment, the electrical therapy has a durationof less than 1 second. In a particular embodiment, the electricaltherapy has a duration less than about one-third of the wavelength ofthe dominant regular oscillation. The electrical activity may beparticularly vulnerable to termination by the therapy when the therapyis delivered at or near the null space commonly found at the tail end ofthe descending slope of the waveform, near baseline, and particularlyduring the early portion of the interoscillation interval.

The null space or “black hole” of oscillations may be found in any of anumber of ways. In one embodiment, the null space may be found bydelivering an electrical pulse of adaptable duration, said pulsebeginning, for example, at the peak of the oscillation or beingtriggered by the oscillation reaching a certain amplitude oracceleration, and continuing until the oscillation(s) is/areterminated). Upon a finding the oscillation has been terminated,delivery of the electrical pulse may be automatically ended. The pulsemay be also terminated if it exceeds a pre-specified duration, if itcauses an adverse (e.g., the oscillation is strengthened) or intolerable(e.g., pain) effect, or if it exceeds a safety limit.

In another embodiment, the null space may be found by delivering aseries of electrical pulses, each pulse of defined duration, beginning,for example, at the peak of the oscillation waveform. The series ofelectrical pulses may be delivered at a frequency slightly lower thanthe oscillation's frequency. For example, if the oscillation is at 25Hz, the electrical pulses may be delivered at a frequency of 24 Hz.Thus, if the first peak of the oscillation is defined to occur at time0, the second peak of the oscillation occurs at time 40 msec, the thirdpeak at time 80 msec, etc. If the first electrical pulse is delivered attime 0, the second electrical pulse may be delivered at time 41.667 msec(if the oscillation was not terminated by the first pulse), the thirdelectrical pulse may be delivered at time 83.333 msec (if theoscillation was not terminated by the second pulse), etc. Futureelectrical pulses of the series would be delivered at increments of1.667 msec after a peak of the oscillation. One electrical pulse in theseries would eventually be delivered at a time after an oscillation peakessentially corresponding to the null space of the oscillation, and thuswould be expected to terminate the oscillation, after which pulsedelivery may be stopped.

Alternatively or in addition, the 24 Hz frequency need not be fixed;further pulses can be delivered at greater or lesser times after anoscillation peak. Alternatively or in addition, a 26 Hz frequency couldbe used, resulting in electrical pulses being delivered in increments of1.667 msec before a peak of the oscillation. All of the particularvalues discussed above are solely by way of example. This disclosureenvisions applicability to other frequencies and/or the use othertechniques, such as dividing the search space, moving backward orforward in the search space, etc.

An epileptic event may comprise oscillations at different frequencieswithin one brain region and/or between multiple brain regions. Differentfrequencies may have different power, as that term is used in the art ofpower spectra. Independently, oscillations at different frequencies mayhave different degrees of regularity, with some being more regular andsome being less.

In one embodiment, wherein an epileptic event may be detected in thebrain of a patient by determining the degree of regularity of theelectrical activity in a first region of the brain of the patient,treating the epileptic event may be performed by applying at least oneelectrical stimulation pulse to at least one neural structure of thepatient for reducing the electrical activity relating to the epilepticevent, in response to the degree of regularity being greater than orequal to a first threshold.

Alternatively or in addition to electrical therapy, any other therapymay be delivered to any target tissue of the subject. In one embodiment,the delivered therapy may comprise one or more of an electrical therapy,a magnetic therapy, a chemical therapy, a heating therapy, a coolingtherapy, applying a positive or a negative pressure to a target tissue,an optical therapy, a cognitive therapy, a sensory therapy, or a motortherapy. The number, locations, functions, and status (active ordormant) of therapy delivery devices (e.g., electrode(s) 282, 283, or284, among others) may vary according to the task at hand.

In a particular embodiment, and regardless of the type of therapydelivered, the stimulation module 275 may be capable of deliveringpulses of energy.

In one embodiment of this disclosure, treatment of an undesirable brainstate such as epileptic seizures, modification of a regularity index orof a phase locking index of epileptic oscillations, may be performed,when required, with energy pulses or “packets”, an approach not found inprior art. The amplitude, duration, shape, inter-pulse interval,(polarity/phases or degree of charge balancing of the parameters forelectrical pulses) of these energy “packets”, may be adapted (toincrease efficacy and/or decreased adverse effects) on- or off-line tothe characteristics, properties or signatures of the epileptic activityunder consideration. For electrical pulses, one or more of theinterpulse interval, amplitude, duration, shape, polarity, of chargebalancing, etc. may each independently vary between individual pulsesand/or between sets of pulses.

These energy pulses or “packets” may be electrical (AC or DC currents),magnetic, chemical (drugs, ions, etc), mechanical (ultrasound, negativeor positive pressure) or thermal (cooling or warming) may be deliveredsingly (e.g., only electrical) or in any possible combination (e.g.,thermal and chemical, or electrical and thermal) either simultaneouslyor sequentially. One of the connotations of “pulse” or “packet” in thisdisclosure is energy “concentrated” into short time windows (e.g.,milliseconds), or continuous delivery of energy over a longer timewindow. For seizure control or treatment, prior art relies on electricalcurrents delivered over time windows (e.g., 1 sec; 10 sec; 30 sec, etc)that are much longer than those that need be used in one embodiment ofthis disclosure. For example, treatment of seizures with electricalcurrents which in prior art is performed with parameters such as 5 mA;100 Hz delivered over 1 sec., (see Osorio et al Ann Neurol, 2005) may beapplied in this disclosure over a much shorter time window (e.g., 100msec), so as to deliver the same energy but at a higher rate. Increasesin rate of delivery of energy, (without exceeding the current densitysafety limit) may be in certain cases and under certain conditions moreefficacious for seizure control than the same energy delivered at aslower rate.

In other embodiments, the same energy may be delivered as continuouslower-amplitude pulse over a longer time period. “Continuous” in thiscontext means that, during the longer time period, the charge is neverequal to zero.

Modification of regularity or of phase locking indices of neuronaloscillations at different temporal or spatial scales, a strategy torender neuronal oscillations amenable to annihilation or to control notexploited in prior art, is also facilitated through the application ofenergy “packets” to neural or non-neural targets.

The functions of the stimulation module 275, the regularity modificationmodule 267, and/or the phase-locking modification module 269, may beperformed by the same unit of the medical device 200.

The medical device 200 may also comprise a stimulation modificationmodule 285. The stimulation modification module 285 may be configured tomodify at least one parameter of an electrical stimulation pulse, basedon an indication the therapy did not have an efficacious result. Inembodiments wherein the medical device 200 may comprise a stimulationmodification module 285, the stimulation module 275 may be configured toapply the modified therapy to at least one neural target.

The magnitude or intensity, duration and whenever applicable extent ofspread of changes in any of the body signal indices (autonomic,neurologic, etc.) may be used to determine their severity and quantifychanges (beneficial or adverse), if any, caused by a therapy such aselectrical stimulation. More information regarding how efficaciousresults of a therapy for an epileptic event may be assessed is given inU.S. patent application Ser. No. 13/280,178.

The medical device 200 may also comprise a stimulation terminationmodule 295. The stimulation termination module 295 may be configured toterminate a therapy, based on an indication the therapy may have anefficacious result. The stimulation termination module 295 may also beconfigured to terminate therapy after a safety duration constraint,e.g., after a predetermined amount of therapy has been applied withoutan efficacious result. The stimulation termination module 295 may alsobe configured to terminate therapy if an adverse effect is detected.

The medical device 200 may also comprise an efficacy and adverse eventmodule 296. The efficacy and adverse event module 296 may determinewhether or not an applied therapy had an efficacious result, an adverseresult, or no result. From this information, the efficacy and adverseevent module 296 may provide information used by the stimulationmodification module 285, the stimulation termination module 295, or bothto perform one or more of their various functions.

More detail regarding stimulation termination and efficacy and adverseevent detection is given by U.S. patent application Ser. No. 13/280,178.

The medical device system of FIG. 2 may also comprise a monitoring unit270, which may be a device that may be capable of transmitting andreceiving data to and from the medical device 200. In one embodiment,the monitoring unit 270 may be a computer system capable of executing adata-acquisition program. The monitoring unit 270 may be controlled by ahealthcare provider, such as a physician, at a base station in, forexample, a doctor's office. In alternative embodiments, the monitoringunit 270 may be controlled by a patient in a system providing lessinteractive communication with the medical device 200 than anothermonitoring unit 270 controlled by a healthcare provider. Whethercontrolled by the patient or by a healthcare provider, the monitoringunit 270 may be a computer, preferably a handheld computer or PDA, butmay alternatively comprise any other device that may be capable ofelectronic communications and programming, e.g., hand-held computersystem, a desktop computer system, a laptop computer system, a server, apersonal digital assistant (PDA), a cellular telephone, etc. Themonitoring unit 270 may download operational data and program softwareinto the medical device 200 for programming the operation of the medicaldevice, and may also receive and upload various status conditions andother data from the medical device 200. Communications between themonitoring unit 270 and the communication unit 260 in the medical device200 may occur via a wireless or other type of communication, representedgenerally by line 277 in FIG. 2.

In one embodiment, the monitoring unit 270 may comprise a local databaseunit 255. Optionally or alternatively, the monitoring unit 270 may alsobe coupled to a database unit 250, which may be separate from monitoringunit 270 (e.g., a centralized database wirelessly linked to a handheldmonitoring unit 270). The database unit 250 and/or the local databaseunit 255 are capable of storing various patient data. These data maycomprise patient parameter data acquired from a patient's body, therapyparameter data, seizure severity data, and/or therapeutic efficacy data.The database unit 250 and/or the local database unit 255 may comprise(contain?) data for a plurality of patients, and may be organized andstored in a variety of manners, such as in date format, severity ofdisease format, etc. The database unit 250 and/or the local databaseunit 255 may be relational databases in one embodiment. A physician mayperform various patient management functions (e.g., programmingparameters for a responsive therapy and/or setting references for one ormore detection parameters) using the monitoring unit 270, which mayinclude obtaining and/or analyzing data from the medical device 200and/or data from the database unit 250 and/or the local database unit255. The database unit 250 and/or the local database unit 255 may storevarious patient data.

One or more of the blocks illustrated in the block diagram of themedical device 200 in FIG. 2 may comprise hardware units, softwareunits, firmware units, or any combination thereof. Additionally, one ormore blocks illustrated in FIG. 2 may be combined with other blocks,which may represent circuit hardware units, software algorithms, etc.Additionally, any number of the circuitry or software units associatedwith the various blocks illustrated in FIG. 2 may be combined into aprogrammable device, such as a field programmable gate array, an ASICdevice, etc.

Turning now to FIG. 3, a stylized block diagram depiction of anelectrical activity zone unit 297 in accordance with one embodiment ofthe present disclosure is illustrated. The electrical activity zone unit297 may comprise an electrical activity mapping unit 310, an electricalactivity coupling/sensing unit 320, a zone gradient unit 330, and anelectrical activity regularity unit 340. The electrical activity zoneunit 297 may be capable of determining coupled electrical activity anddetermining zones or areas of electrical activity (e.g., seizureactivity) in a patient's brain. The electrical activity zone unit 297may be capable of determining if at least one zone of electricalactivity in the brain may be correlated or coupled at least partially toat least one other zone of electrical activity.

The electrical activity mapping unit 310 may be capable of mapping(e.g., “localizing”) the sites(s) of origin of various electricalactivities in a patient's brain. The mapping may be based upon priordata, reference data, and/or real time or near real time data. In oneexample, the electrical activity mapping unit 310 may generate athree-dimensional mapping of a patient's brain as exemplified in FIG. 4(described in further detail below). Generally, various types ofelectrical activity taking place in a patient's brain may be mapped.Referring simultaneously to FIGS. 3 and 4, FIG. 4 illustrates a stylizeddepiction of a three-dimensional mapping of electrical activity in apatient's brain. The electrical activity coupling/sensing unit 320 maybe capable of determining one or more relationships between one or moredetected electrical activities. For example, based upon data relating tothe electrical activity, two or more electrical activities may becorrelated if a determination may be made that those two instances ofelectrical activities are coupled (e.g., phase-locked) in some fashionor degree. This coupling may include a variety of relationships betweenelectrical activities, such as a first electrical activity initiating asecond electrical activity. Other types of relationship may includephysiological similarities between the electrical activities, etc.

The zone gradient unit 330 may determine any gradient associated withany detected electric activity. As such, spread of electrical activitymay be mapped/tracked or predicted based upon an expected gradientand/or an observed or actual gradient. The zone gradient unit 330 mayuse data from the electrical activity mapping unit 310 and/or theelectrical activity unit coupling/sensing unit 320 to determine agradient or a potential gradient between brain regions. As exemplifiedin FIG. 4, the various mapping, coupling and gradient information may beplotted on a three-dimensional graph representing a patient's brainand/or regions and/or subregions thereof.

The electrical activity regularity unit 340 may be capable ofregularizing electrical activity in at least one region or subregion ofthe patient's brain. Based upon information from the electrical activitymapping unit 310 and/or the zone gradient unit 330, the electricalactivity regularity unit 340 may determine that the un-coupled orunrelated electrical activities in a patient's brain may be regularizedbefore applying a stimulation signal to attenuate or block the activity.Based upon one or more characteristics of the electrical activities, theelectrical activity regularity unit 340 may determine one or moreparameters of a signal that may be used to regularize at least oneelectrical activity in the patient's brain and/or a region and/orsubregion thereof. The degree of regularity may be based upon one ormore of a measure of amplitude variance, a measure of frequencyvariance, a measure of zero-crossings interval variance, a measure ofascending and descending slope variances, a number of extrema, apolarity of extrema, a box counting method, a polynomial fitting tomeasure the error of polynomial approximation, a Lipschitz exponent ofone of the foregoing, or a Holder exponent of one of the foregoing.

Alternatively or in addition, an unsupervised correlation-basedclustering method may be applied (with appropriate modifications asrequired by this disclosure) to cortical signals to determine theirdegree of regularity (J Neurosci Methods. 2009; 178:228-36).Subsequently, a medical device 200 may deliver an electrical signal,e.g., a pulse signal, to attenuate or entirely diminish two or more ofthe electrical activities. In this manner, for example, two or moreseizure activities in a patient's brain may be attenuated, even thoughthe seizure activities were substantially de-coupled at seizure onset.The electrical activity regularity unit 340 may utilize look-up featuresand/or calculate features to determine the potential for regularizing atleast two areas of electrical activity, and attenuate the electricalactivities based upon regularizing them.

Nonlinear delayed feedback stimulation (Biol Cybern 2006; 95:69-85; PhysRev Lett 2005; 94164102; Phys Rev E Stat Nonlin Soft Matter Phys 2010;82(2 Pt 2):026204) robust against variations of system parametersrepresenting an intermixture of activities recorded from the regions ofinterests using macro-electrodes may be used for signal modification ortreatment purposes. Phase model analysis combined with calculus ofvariation may be used to derive a waveform with which to entrainneuronal oscillations. Optimal waveforms are calculated from the phaseresponse curve and a solution to a balancing condition.

In other embodiments (not shown), the medical device 200 mayalternatively or in addition comprise a chemical activity zone unit, athermal activity zone unit, or a mechanical activity zone unit, amongothers, having internal units similar to the electrical activity mappingunit 310, electrical activity coupling-sensing unit 320, zone gradientunit 330, and/or electrical activity regularity unit 340.

Turning now to FIG. 4, a graphical depiction of a mapping of electricalactivity in a patient's brain, in accordance with one embodiment of thepresent disclosure, is illustrated. The mapping of electrical activitylocations 410, 420, and 430 depict electrical activity that are likelyto be coupled or related to each other. For example, the electricalactivity locations 410, 420 and 430 (represented by filled-in circles)may be seizures in brain regions and/or subregions that arerelated/coupled to each other as a result of spread from or entrainmentby one region to another. The electrical activity areas 460, 470 and 480(represented by filled-in squares) depict areas of electrical activitythat are likely not coupled or are independent of each other. Theseelectrical activity areas may be mapped by the electrical activity zoneunit 297 in one embodiment.

Moreover, in addition to determining an actual gradient relating toelectrical activities, the electrical activity zone unit 297 may be alsocapable of determining a potential gradient relating to one or moreelectrical activity locations. For example, a first gradient 490 fromthe electrical activity 410 and a second gradient 491 from theelectrical activity 420 may be identified by the electrical activityzone unit 297. Based upon an analysis of the gradient, the electricalactivity zone unit 297 may be capable of determining a potential newsite of electrical activity (450, 440) as depicted by the un-filled,dotted circle in FIG. 4. The gradients 490, 491 may be determined inorder to determine potential future new electrical activity areas thatwould be coupled with or related to the detected electrical activities410, 420, and/or 430.

The medical device 200 may utilize the electrical activity mappinginformation depicted in FIG. 4 to treat electrical activity area, avoidunnecessary treatment of dissimilar or unrelated electrical activityregions, and/or target potential new electrical activity areas fortreatment. In this manner, the existing electrical activity, such asepileptic events, may be treated by targeting specific areas of thebrain. Further potential new areas of seizure activities may be treatedsuch that the possibility of seizure activity may be diminished.

The targeting of particular areas of abnormal or undesirable electricalactivity and/or potentially abnormal or undesirable electrical activitymay be made for treatment in a number of ways that would be known tothose skilled in the art having benefit of the present disclosure. FIGS.5A and 5B illustrate one such example. Turning now to FIGS. 5A and 5B, astylized depiction of a sensor/electrode array mesh 510, in accordancewith one embodiment of the present disclosure, is illustrated. FIG. 5Adepicts a sensor/electrode array 520 that may be embedded or integratedinto the array mesh 510. The sensor/electrode array mesh 510 is depictedas a mesh-type unit for illustration purposes only and those skilled inthe art would be able to implement a variety of types ofsensor/electrode arrays and remain within the spirit and scope of thepresent disclosure. The array mesh 510 may comprise a plurality ofsensors and/or electrodes positioned in any number of configurations,such as a row-column array.

FIG. 5B illustrates a top view of the array mesh 510, in accordance withone embodiment of the present disclosure. The array mesh 510 may beformed such that a predetermined arrangement of sensors and electrodesare configured in a manner such that various portions of the brain maybe targeted for treatment/stimulation. The sensors/electrodes array 520may include positioning the sensors and electrodes such that theycontact with various portions of a person's skull, targeting specificlocations in the brain. Alternatively, the sensors/electrodes array 520may include sensor and electrode elements that are capable ofeffectuating dermal or subcutaneous contact. The arrays may beinterconnected electrically via wires 530 that may be coupled to anexternal device that can provide control signals and/or power forcontrolling the operations of the sensor/electrode array mesh 510. Inthis manner, the various mapped locations of electrical activity and/orpotential electrical activity described in the context of FIG. 4, may betargeted for treatment. Data from the electrical activity zone unit 297may be sent to a processing unit within a medical device to control theactivation of various sensors and/or electrodes in the sensor/electrodearray mesh 510, thereby being capable of providing targeted treatmentfor regularizing and diminishing electrical activity and/or reducing thepossibility of the occurrence of electrical activity in a patient'sbody.

The one or more of the sensors/electrodes of sensors/electrodes array520 may be used for sensing, modification of regularity or phase-lockingindices, and/or for delivery of a therapy. Electrodes suitable for thisapplication include, but are not limited to, those described in U.S.patent application Ser. No. 11/151,386. Other electrodes suitable forthis application include, but are not limited to, scalp electrodes orbrain implanted electrodes, such as depth electrodes or ECoG electrodes.

FIG. 6 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure. In the depictedmethod, an epileptic event may be detected at 610. In one exemplaryembodiment, detecting the epileptic event may comprise detecting atleast one of a cardiac activity indicative of an epileptic event or abody movement indicative of an epileptic event. In another exemplaryembodiment, detecting the epileptic event may comprise detecting anelectrical activity indicative of an epileptic event in a brain regionof a patient.

After the detecting at 610, a degree of regularity, such as a regularityindex, of electrical activity may be determined in a first brain regionof a patient at 615. The degree of regularity may be determined from anautocorrelation function, a template-matching function, a varianceanalysis, fractal analysis, a Hurst exponent estimation, etc. In anexemplary embodiment, the degree of regularity may be determined basedon at least one of a measure of autocorrelation, a measure of amplitudevariance, a measure of frequency variance, a measure of zero-crossingsinterval variance, a measure of ascending and descending slopevariances, a number of extrema, a polarity of extrema, a polynomialfitting to measure the error of polynomial approximation, a box countingmethod, a Lipschitz exponent of one of the foregoing, a Holder exponentof one of the foregoing, or two or more thereof.

Thereafter, a determination may be made at 620 whether the degree ofregularity is inside a first range. The value of the range may be set toany range of values found to be effective in this method. In aparticular embodiment, the degree of regularity is determined from aregularity index having a set of possible values of 0.0-1.0, and thefirst range may have as a lower bound any value from 0.3 to 0.7, such as0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, or 0.7, among others, andmay have as an upper bound any value from 0.6 to 1.0, such as 0.6, 0.65,0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1.0, provided the selected upperbound is greater than the selected lower bound.

In one particular embodiment, wherein the regularity index is determinedfrom an autocorrelation function, the first range is 0.6-1.0

If the degree of regularity is greater than or equal to the firstthreshold, at least one electrical stimulation may be applied to atleast one neural target of the patient for treating the epileptic event,at 630.

The electrical stimulation may be applied at any time during theepileptic event. In one embodiment, the electrical stimulation may beapplied at a downslope, zero crossing of at least one neuronal activityoscillation of the brain of said patient.

In an exemplary embodiment, the electrical stimulation may comprise oneor more electrical stimulation pulses. The electrical stimulation may beconsidered an electrical signal. An electrical stimulation, electricalstimulation pulses, and an electrical signal may have a number ofparameters discussed above. In one embodiment, an electrical signal mayhave a programmed on-time. In one embodiment, an electrical pulse mayhave a programmed pulse width.

The neural target to which therapy may be applied may be at least one ofthe patient's brain, a target portion of the patient's brain, a cranialnerve of the patient, or a target portion of the cranial nerve of thepatient. In one embodiment, an electrical therapy may be applied to afirst target area in at least one of a brain region or a cranial nerveof the patient.

Control of seizures as taught in prior art, is through delivery ofelectrical currents at a single frequency (e.g., 100 Hz.), an approachthat may be efficacious if seizures' oscillations are highly regularand/or phase-locked/aligned. Unlike prior art, this disclosure takesinto account the importance of these factors (regularity and/or phaselocking/alignment) in determining the probability of therapeuticefficacy and therefore includes them in treatment algorithms.

Modification of the regularity or of the phase locking indices ofneuronal oscillations through entrainment or phase resetting, may beperformed using known techniques or methods. In one embodiment of thisdisclosure, entrainment may be achieved by applying simultaneouslyenergy “packets” at several frequencies. For example, electricalcurrents may be delivered as sine waves at 0.001 Hz upon which sinewaves at lower frequencies (e.g., [0.00001, 0001, 0.001 Hz, 0.1 Hz, 1Hz, 10 Hz, 100 Hz, 1000 Hz) are superimposed to create a “fractal”energy pulse. The fractal may be pure or statistical. Entrainment ofneuronal physiologic or pathologic neuronal oscillations may be easierto achieve if the frequency of the entraining oscillations is similar orhas a certain harmonic relation to the frequency of the oscillations tobe entrained. That is, the success of entrainment may be dependent onthe state of the brain and on the spatial scale at which it should beachieved. Entrainment during slow wave sleep, a state during whichoscillations in the delta band (e.g., 1-3 Hz) are predominant, is morelikely to occur if the entraining oscillations' frequency band is delta.“Steady” (in reality they change very slowly) differences in potentialmay be recorded between cortical regions, differences that bear acertain correlation with faster neuronal oscillations as recorded withthe EEG or ECoG using conventional (e.g., 1-70 Hz) filter settings.Prior art aimed at seizure control overlooks these “steady” corticalpotential differences known as “infra-slow” (0.5-2 cycles/min; 1-1.5cycles/min) oscillations, which bias the behavior (excitability level)of neurons in the region over which they spread or of distant regionsconnected to that over which they spread.

FIG. 14 depicts infra-slow rhythms of brain electrical activity (Nature1957; 179: 957-59). Trace 1: motor cortex, 8 min⁻¹. Trace 2: striatecortex, 1-7 min⁻¹. Traces 3a and 3b: before and after strychninepoisoning. Traces 4a and 4b: before and after prolonged irritation ofthe hypothalamus. Traces 5a and 5b: before and two hours after injectionof luminal. Trace 6a: sensory cortex (superficial). Trace 6b: sensorycortex (1-2 mm depth). Trace 7: Trace 1 with increased speed andamplification.

By way of example, the role of infra-slow or of slow oscillation on theemergence of fast cortical oscillations (“spindles”) as shown in FIG.14, Trace 7, is temporally restricted to the rising phase of theinfra-slow oscillations (FIG. 14, Traces 1-2) and more specifically whenthis phase is negative in the frontal relative to the posterior regions.

While FIG. 14 does not contain examples of epileptic activity, it isshown here to emphasize the role that slow (about 0.1-3 Hz) andinfra-slow oscillations (less than about 0.1 Hz) play on determiningbrain excitability and the emergence of the fast frequencies (e.g., betaand gamma waves, about 14-45 Hz) that characterize seizures as recordedusing conventional (e.g., 1-70 Hz) filter settings. The role of slow andinfra-slow oscillations in conventional EEG/ECoG settings are usuallyignored because of the filter settings applied to them. ConventionalEEG/ECoG filter settings remove much information outside of 1-70 Hz.Typically, unless they reach a certain amplitude, oscillations between0.1 Hz and 1 Hz may be unrecordable with a 1 Hz low frequency filter.Thus, primarily only the fast frequencies are seen and slow andinfraslow oscillations are filtered out. The fast frequencies often“ride” on slow or infra-slow waves that are not visible due to thefilter (e.g., 1 Hz) applied to the signal.

The probability of having similar values in regularity and phaselocking/alignment in a given regions or regions, is a function of degreeof coupling (anatomical, electrical or chemical) within or between saidregions, being higher for regions highly coupled than for regions thatare weakly coupled or uncoupled. Coupling between regions may change aselectrical or chemical changes spread across the neuropil; thosemediated by infra-slow or slow oscillations encompass larger regionsthat those mediated by faster frequency oscillations.

Similar considerations apply to even slower oscillations, such as thoseon ultradian, circadian, and menstrual timescales.

If the degree of regularity is determined at 620 to be outside the firstrange, then the degree of regularity of the electrical activity may bemodified at 640. The degree of regularity may be modified by delivery ofa neuronal regularization electrical stimulation to the first brainregion, at least one second brain region connected to the first brainregion, or both. The neuronal regularization electrical stimulation maycomprise at least one entraining pulse. The neuronal regularizationelectrical stimulation may comprise one electrical stimulation pulse ora plurality of electrical stimulation pulses. Drug pulses, thermalpulses, or other techniques may be used to modify the degree ofregularity of a brain region(s)′ oscillations.

Those skilled in the art appreciate that modification and/or abatementof undesirable cortical oscillations may be performed non-invasively(e.g., from the scalp) by delivering transcranial electricalstimulation/currents or magnetic stimulation to a neural or non-neuraltarget, for the purpose of exerting a beneficial effect either directlyto said region or indirectly to regions connected to said target,effects that may outlast the duration of current delivery.

The parameters of the neuronal regularization electrical stimulation maybe determined by a physician during work-up of the patient, or may befound by traversing the search space during performance of the method.For example, during the first loop through 640, the electrical activitymay have a first degree of regularity R₁. A first neuronalregularization electrical stimulation may then be delivered to effect achange at 640. Upon return of flow to element 620 via element 615, theelectrical activity may have a second degree of regularity R₂. If R₂ isoutside the first range but is closer to the nearest bound of the firstrange than was R₁, the properties of the first neuronal regularizationelectrical stimulation may be considered to have improved the degree ofregularity and may be used as a basis for establishing the properties ofa second neuronal regularization electrical stimulation. If R₂ isoutside the first range and further from the nearest bound of the firstrange than was R₁, the properties of the first neuronal regularizationelectrical stimulation may be considered to have impaired the degree ofregularity, and other properties may be used as a basis for establishingthe properties of a second neuronal regularization electricalstimulation.

The modification at 640 is optional. In other embodiments, if the degreeof regularity is outside the first range, flow may return to determiningthe degree of regularity at 615. The degree of regularity of anelectrical activity is likely to change over the course of an epilepticevent. For example, FIG. 11 shows ECoG seizure data collected from apatient with epilepsy using electrodes located at a left subtemporalanterior (LSTA) position over 30 sec of a seizure suffered by thepatient. As can be seen, the EEG data varied from qualitatively lessregular (e.g., at 0 to 5 sec) to qualitatively more regular (e.g., at 20to 30 sec) over the course of said epileptic event. The present inventorhas also observed data varying from qualitatively more regular toqualitatively less regular during epileptic events.

Periodic determination of the degree of regularity at 615, such as at arate of at least 4 times per second, followed by the determination at620, may eventually reveal a degree of regularity inside the first rangein the absence of any modification at 640.

In another embodiment, if the degree of regularity of the electricalactivity in the first brain region is outside of the first range,another regularity index or other measure of regularity may bedetermined for another electrical activity in a sub-region of the firstbrain region. It may be that the other electrical activity has anotherregularity index inside a second range (which may have the same boundsas the first range, or may have different bounds), wherein such regularelectrical activity in the sub-region is sufficient to make applying at630 likely to be efficacious in treating the epileptic event. If theother electrical activity has another regularity index outside thesecond range, a modifying stimulation, such as an electricalstimulation, may be delivered to a neural target to make the otherelectrical activity more regular and the epileptic event more amenableto efficacious therapy.

For example, under certain conditions, highly regular (e.g., regularityindex=0.85) neuronal oscillations may be an “intermixture” or“admixture” of highly regular oscillations with different frequencies.FIG. 13 depicts a neural region (C) and two sub-regions (A and B), eachgenerating highly regular oscillations but at different frequencies(tracings from A and B) than when recorded with a sensor thatsimultaneously acquires data from both regions appear intermixed(tracing from C).

Determination of the regularity index on these oscillations would revealas many “peak” values as there are regular frequencies; in the exampleof FIG. 13, there are two regularity index values of 0.9 indicative ofhighly regular oscillations at two different frequencies that whenrecorded with a single electrode that spans both sub-regions, appear asan “admixture” with two high regularity index values. The implication,for therapeutic purposes, of having two or more high regularity indexvalues (instead of a single one) in a time window, is that unlessmodified or “subsumed” into a single highly regular frequency, two ormore energy pulses properly timed, may be desirable to treat the two ormore oscillations.

FIG. 7 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure. FIG. 7 has someelements in common with FIG. 6, and those common elements need not bedescribed again.

FIG. 7 shows, after determining a degree of regularity at 615, a furtherstep is taken at 720 to determine if there are epileptic oscillations atother frequencies with multiple degrees of regularity.

This point may be illuminated by reference to FIG. 12A-12B. Thesefigures show a large circle depicting a neural structure (e.g., thebrain, one of its lobes, a region within one of its lobes, or asub-region within a region, etc.), whose activity is recorded atmultiple sites (smaller circles or squares), spatial scales, and/or timescales. Regularity index values may differ or be similar between closelyspaced regions with different cytoarchitecture or within a region withhomogenous cytoarchitecture (FIG. 12A).

Multiple degrees of regularity may arise simultaneously or sequentiallyin different brain regions (e.g., regions A and B of FIG. 12A) ordifferent brain sub-regions within the same region (e.g., subregions Cand D of FIG. 12A).

If the determination at 720 finds there is only one degree of regularityfor the patient's epileptic activity, a determination can be madewhether it is inside a first range at 620, which may be followed bysubsequently applying and/or modifying at 630 and/or 640.

If there are multiple degrees of regularity inside the first range, oneor both of the following may be performed at 735. First, at least one ofthe degrees of regularity may be modified, similarly to themodifications discussed above at 640. For example, of the electricalactivities depicted in FIG. 12A, activities in region B and subregion Dcould be made more regular. Second, multiple electrical stimulations maybe applied. Each of the electrical stimulations applied at 735 may bechosen to treat one of the regular oscillations having a degree ofregularity found at 720. Continuing the example of FIG. 12A, oneelectrical stimulation or other therapy could be applied to treat theactivity in region A, and a second electrical stimulation or othertherapy could be applied to treat the activity in sub-region C.

As with the regularity index value, phase locking/alignment index valuesmay differ or be similar between closely spaced regions with differentcytoarchitecture or within a region with homogenous cytoarchitecture(FIG. 12B).

FIG. 8 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure. In the depictedembodiment, an epileptic event, including its number of origin sites,may be detected in at least one brain region of a patient, at 810.Detecting the epileptic event may be performed using any techniquediscussed herein. Determination of the number of epileptogenic sites orloci may then be made at 820.

However, if there are multiple origin sites, the degree of regularity ateach site may be determined at 830. Techniques for doing so have beendescribed elsewhere herein. As discussed above and shown in FIG. 12A,multiple degrees of regularity may arise simultaneously or sequentiallyin different brain regions or different brain sub-regions within thesame region.

It may be determined at 850 whether the degrees of regularity are eachwithin a first range. For example, FIG. 12B depicts three oscillations,numbered 1-3, which are each highly regular. If the degrees ofregularity are not all within the first range, then at least one or moreof them may be modified at 852, making use of techniques describedelsewhere herein. If the degrees of regularity are all within the firstrange (such as in the example shown in FIG. 12B), then a phaserelationship between the epileptic activity at the multiple sites may bedetermined at 854. Whether the epileptic activity is phase-locked may bedetermined at 860. Continuing the example of FIG. 12B, all three of theoscillations 1-3 are phase-locked; the phase difference remains constantover a time period, such as the time between time α and time β. Phasealigned means two oscillations are phase locked, with negligible phasedifference.

FIG. 13 shows another example of epileptic activity having two differentfrequencies but identical degrees of regularity as shown in regions Aand B. Having found that the regularity indices in sub-regions A and Bare within a first threshold, a decision may be made to determine theirdegree of phase locking before delivering therapy pulses; if theoscillations in both regions are phase-locked and there is alsosubstantial phase alignment between the two frequencies, therapy pulsesmay be delivered synchronously to both regions. If they are phase lockedbut not aligned, therapy pulses with differences in the timing ofdelivery reflective of the phase difference between the two frequenciesmay delivered or modification (e.g. alignment) pulses may be appliedbefore delivery of therapy pulses if the oscillations' conditionswarrant it.

Returning to FIG. 8, the determination at 860 may find the epilepticactivity is not phase-locked. If so, a phase-locking stimulus may bedelivered at 862.

On the other hand, if the determination at 860 finds the epilepticactivity is phase-locked, it may still be not amenable to treatment witha single treatment stimulation. For example, in FIG. 12B, one treatmentstimulation about one-third of a wavelength after α would be likely toterminate oscillations 2 and 3, but would be unlikely to terminateoscillation 1. Thus, a determination as to whether the epilepticactivity is phase-aligned may be made at 870.

From the determination at 870, it may be found the epileptic activity atthe various sites is phase-aligned. In this situation, a singletreatment stimulation that is conducive to treating the epilepticactivity at one site may also be conducive to treating it at the othersites. Thus, a treatment stimulation may be delivered at 874.

On the other hand, the determination at 870 may find the epilepticactivity at the various sites is not phase-aligned. It is phase-locked,meaning that a plurality of treatment stimulations, one for each lockedphase, may be delivered at 872, preferably as much out of phase from oneanother as the various epileptic activity tracings are out of phase fromone another. For example, in FIG. 12B, one treatment stimulation atabout α would be likely to terminate oscillation 1, and a secondtreatment stimulation about one-third of a wavelength after α would belikely to terminate oscillations 2 and 3, thus terminating all threeoscillations.

Alternatively or in addition, a phase-aligning stimulation may bedelivered at 872, such that the epileptic activity at the various sitescomes into phase alignment.

FIG. 9 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure. In the depictedmethod, an epileptic event in at least a first brain region of a patientmay be detected at 912. The regularity of electrical activity relatingto the epileptic event in the first brain region may be modified at 918,if necessary (e.g., if it is outside a first range). At least oneelectrical stimulation pulse may be applied to at least a first neuraltarget of the patient for reducing said electrical activity relating tosaid epileptic event, at 930. Detecting the epileptic event, increasingregularity of electrical activity, and applying at least one electricalstimulation pulse may be performed using any technique(s) discussedherein.

Upon application of at least one electrical stimulation pulse to the atleast first neural target, a response of the epileptic event to theelectrical stimulation may be assessed at 950. Assessment of theresponse may be performed using any technique(s) discussed herein. Inone embodiment, a body signal indicative of the epileptic event'sresponse to the therapy may be received. In one embodiment, the bodysignal may be an autonomic signal. In another embodiment, the bodysignal may be a neurologic signal. In one embodiment, the body signalmay be a metabolic signal. In another embodiment, the body signal may bean endocrine signal. In one embodiment, the body signal may be a tissuestress marker signal. In one embodiment, the body signal may be acognitive signal. The body signal may be selected from one or more ofthe foregoing.

Exemplary autonomic signals that may be detected include, but are notlimited to, a cardiac signal, skin resistance, a respiratory signal, anoutput (e.g., number of spikes/unit time; pattern of spikes, amplitudeof spikes, etc.) from a parasympathetic or from sympathetic tissue, thepatient's body temperature, or an infrared activity of a portion of thepatient's body, among others.

Exemplary neurologic signals that may be detected include, but are notlimited to, a motor activity signal, or a cognitive signal, amongothers.

Exemplary metabolic signals that may be detected include, but are notlimited to, an arterial and/or venous blood pH, lactic acidconcentration of the patient's blood, a pyruvic acid concentration ofthe patient's blood, or a potassium concentration of the patient'sblood, among others.

Assessing the response at 950 may comprise determining whether thetherapy gave an efficacious result against the epileptic event. An“efficacious result” may be demonstrated by a change in an efficacyindex, an observation of improvement or termination of the epilepticevent, or the like. In one embodiment, the assessment at 950 maycomprise determining an efficacy index based upon a body signal.

A response may be assessed at any time. For example, a response may beassessed after applying the electrical therapy at 930 for apredetermined duration. For another example, a response may be assessedafter applying the electrical therapy at 930 for less than apredetermined duration said predetermined duration being for example theduration of a therapy.

If the assessment reveals a beneficial change in the epileptic event at960, e.g. a positive response, an efficacious result, a high and/orincreased efficacy index, an improvement in the epileptic event, atermination of the epileptic event, or two or more thereof, delivery ofthe electrical stimulation pulse may be terminated at 990. Terminationmay alternatively or in addition be based upon at least one of exceedinga predetermined number of delivered electric stimulation pulses,exceeding a predetermined electrical stimulation duration, or exceedinga predetermined current density. Termination of a therapy may also occurin response to the determination that the therapy causes an adverseeffect said effect including but not being limited to increasing theseverity of a seizure and/or degrading any body system's function asdetermined using cerebral or extra-cerebral body signals, posing safetyrisks or causing intolerable effects.

If the therapy comprises at least one electrical pulse, terminating thetherapy may comprise not delivering another pulse. Alternatively or inaddition, terminating a therapy comprising at least one electrical pulsehaving a programmed pulse width may comprise terminating delivery of theelectrical pulse prior to the end of the programmed pulse width.

The therapy may be continued indefinitely. In another embodiment, thetherapy may be continued for a predetermined duration. The predeterminedduration may be selected to result in termination of the application ofthe therapy after a safety duration, i.e., therapy may be terminated toreduce the likelihood of injury to the tissue to which the therapy isapplied or to preserve battery life of a device, among other reasons. Inanother embodiment, if an adverse effect of the therapy is detected,application of the therapy may be terminated.

If a beneficial change in the epileptic event is not indicated, whichmay include no change in the epileptic event or an adverse effect of thetherapy, the application of the therapy may be continued, as shown inFIG. 9 by the flow line from 960 to 930. For example, a lack of abeneficial change may be indicated by a finding an efficacy index may beless than an efficacy threshold, and the therapy may be continued inresponse to such a finding.

In one embodiment, if a beneficial change is not indicated, the therapymay be modified at 970. Modifying the therapy at 970 may comprisemodifying at least one parameter of the therapy, such as (for anelectrical therapy) a waveform, a pulse width, a number of pulses, aninter-pulse interval, an amplitude, a phase, a polarity, a timing oftherapy delivery relative to a zero-crossing, a timing of the therapydelivery relative to an extremum, or a timing of the therapy deliveryrelative to a region of an ascending or descending slope of a neuronaloscillation, among others. Modifying the therapy at 970 may alsocomprise changing therapy modalities (e.g., from electrical to chemical,thermal, etc.). Modification of a therapy may also occur in response tothe determination that the therapy causes an adverse effect said effectincluding but not being limited to increasing the severity of a seizureand/or degrading any body system's function as determined using cerebralor extra-cerebral body signals, posing safety risks or causingintolerable effects.

The modifying at 970 may comprise modifying the therapy as a function ofat least one of an efficacy index value or a direction of change of anefficacy index value.

In other embodiments, modifying a therapy at 970 may be performedaccording to a predetermined schedule, in response to an external input,or both, alone or in combination with any other modifying technique.

In one embodiment, if the therapy has a predetermined duration,modifying the therapy at 970 may be performed prior to the end of thepredetermined duration.

If modifying is performed at 970, the modified therapy may be deliveredat 980. Thereafter, the assessing at 950, modifying at 970, anddelivering at 980 may be repeated as needed, until a beneficial changeis found at 960, or another ground for terminating delivery of thetherapy arises.

Any method depicted in FIGS. 6-9 may be performed by a non-transitive,computer-readable storage device for storing instructions that, whenexecuted by a processor, perform the method.

All of the methods and apparatuses disclosed and claimed herein may bemade and executed without undue experimentation in light of the presentdisclosure. While the methods and apparatus of this disclosure have beendescribed in terms of particular embodiments, it will be apparent tothose skilled in the art that variations may be applied to the methodsand apparatus and in the steps, or in the sequence of steps, of themethod described herein without departing from the concept, spirit, andscope of the disclosure, as defined by the appended claims. It should beespecially apparent that the principles of the disclosure may be appliedto selected cranial nerves other than, or in addition to, the vagusnerve to achieve particular results in treating patients havingepilepsy, depression, or other medical conditions.

The particular embodiments disclosed above are illustrative only. Thedisclosure may be modified and practiced in different but equivalentmanners. Furthermore, no limitations are intended to the details ofconstruction or design herein shown other than as described in theclaims below. It is, therefore, evident that the particular embodimentsdisclosed above may be modified and all such variations are consideredwithin the scope and spirit of the disclosure. Accordingly, theprotection sought herein is as set forth in the claims below.

What is claimed:
 1. A non-transitive, computer-readable storage devicefor storing instructions that, when executed by a processor, perform amethod, comprising: detecting, in at least a first brain region of apatient, an electrical activity relating to an epileptic activity,determining a first regularity index of said electrical activity; andapplying at least one first electrical stimulation to at least oneneural target of said patient for treating said epileptic event, inresponse to said first regularity index being within a first range. 2.The non-transitive, computer-readable storage device of claim 1, whereinthe method further comprises: detecting, in at least a second brainregion of a patient, a second electrical activity relating to anepileptic activity; determining a second regularity index of said secondelectrical activity; determining a phase-locking index between saidfirst brain region and a second brain region of the patient if saidfirst regularity index and said second regularity index are both withinsaid first range; and applying at least one second electricalstimulation to at least one neural target of said patient for treatingsaid epileptic activity, in response to said phase-locking index beingwithin a second range.
 3. The non-transitive, computer-readable storagedevice of claim 2, wherein the method further comprises: determiningwhether said second electrical stimulation was not efficacious or causedan adverse reaction; determining at least a third regularity index of atleast one of said first electrical activity or said second electricalactivity in response to determining said second electrical stimulationwas not efficacious or caused an adverse reaction.
 4. Thenon-transitive, computer-readable storage device of claim 1, whereinsaid at least one first electrical stimulation has a duration less thanabout one-third of the dominant wavelength of said first electricalactivity.
 5. The non-transitive, computer-readable storage device ofclaim 1, wherein said first regularity index comprises informationrelating to the oscillation morphology, amplitude, and frequency of saidfirst electrical activity.
 6. The non-transitive, computer-readablestorage device of claim 1, wherein said determining comprisesdetermining said first regularity index for a window comprising from twoto twenty wavelengths of a predominant oscillation of said firstelectrical activity.
 7. The non-transitive, computer-readable storagedevice of claim 1, wherein the method further comprises selecting atleast one frequency component from said first electrical activity; andwherein said first regularity index is determined at least in part onsaid frequency component.
 8. The non-transitive, computer-readablestorage device of claim 7, wherein said frequency component has afrequency within a range selected from 1-6 Hz, 8-45 Hz, 1-200 Hz, DC to100 Hz, 100-1000 Hz, or DC to 1000 Hz.
 9. The non-transitive,computer-readable storage device of claim 1, wherein the method furthercomprises repeating said detecting and determining at a rate of at least4 times per second.
 10. The non-transitive, computer-readable storagedevice of claim 1, wherein the method further comprises: applying atleast a third electrical stimulation to at least one neural target tomodify said first regularity index if said first regularity index isoutside said first range.
 11. The non-transitive, computer-readablestorage device of claim 10, wherein the method further comprises:redetermining said first regularity index after said applying said atleast one third electrical stimulation; and reapplying said at least onethird electrical stimulation if said redetermined first regularity indexis outside said first range.
 12. The non-transitive, computer-readablestorage device of claim 10, wherein said first regularity index isdetermined by an autocorrelation function of said electrical activity,and said first range is 0.6-1.
 13. The non-transitive, computer-readablestorage device of claim 1, wherein determining said first regularityindex is based on at least one of a measure of autocorrelation, ameasure of amplitude variance, a measure of frequency variance, ameasure of zero-crossings interval variance, a measure of ascending anddescending slope variances, a number of extrema, a polarity of extrema,a polynomial fitting to measure the error of polynomial approximation, abox counting method, a Lipschitz exponent of one of the foregoing, or aHolder exponent of one of the foregoing.
 14. The non-transitive,computer-readable storage device of claim 7, wherein said firstregularity index is determined based on a power spectral density of saidfirst electrical activity or a power level of said frequency component.15. The method of claim 7, wherein said first regularity index isdetermined based on said frequency component, independent of a powerlevel of said frequency component.
 16. The non-transitive,computer-readable storage device of claim 1, wherein the method furthercomprises: assessing a response of said epileptic event to said at leastone first electrical stimulation; modifying at least one parameter ofsaid at least one first electrical stimulation, if said responsecomprises a lack of a beneficial effect, an adverse effect, or both; anddelivering said modified first electrical stimulation to at least oneneural target of said patient.
 17. The non-transitive, computer-readablestorage device of claim 1, wherein the method further comprises:determining a fourth regularity index of electrical activity relating tosaid epileptic activity in at least a sub-region of said first brainregion; applying at least a fourth electrical stimulation to at leastone neural target to modify said fourth regularity index, if said fourthregularity index is outside a second range.
 18. A non-transitive,computer-readable storage device for storing instructions that, whenexecuted by a processor, perform a method, comprising: detecting a firstelectrical activity relating to a first epileptic activity in at least afirst brain sub-region of a patient; detecting a second electricalactivity relating to a second epileptic activity in at least a secondbrain sub-region of said patient; determining a phase-locking indexbetween said first electrical activity and said second electricalactivity; applying at least one first electrical stimulation to at leastone neural target of said patient for treating said epileptic activity,in response to said phase-locking index being inside a first range. 19.The non-transitive, computer-readable storage device of claim 18,wherein the method further comprises: assessing a response of saidepileptic activity to said at least one first electrical stimulation;modifying at least one parameter of said at least one first electricalstimulation, if said response comprises a lack of beneficial change, anadverse change, or both; and delivering said modified at least one firstelectrical stimulation to at least one neural target.
 20. Thenon-transitive, computer-readable storage device of claim 18, furthercomprising: applying at least a second electrical stimulation to atleast one neural target to modify said phase-locking index if saidphase-locking index is outside a second range.
 21. The non-transitive,computer-readable storage device of claim 20, wherein said applicationof said second electrical stimulation to modify said phase-locking indexfurther comprises promoting phase alignment between said firstelectrical activity and said second electrical activity.
 22. Thenon-transitive, computer-readable storage device of claim 18, wherein atleast: one parameter of said electrical stimulation, a number of saidneural targets, a location of said neural targets, or two or morethereof; is based on the degree of phase alignment between said firstelectrical activity and said second electrical activity.
 23. Thenon-transitive, computer-readable storage device claim of 21 whereinsaid promoting phase-alignment comprises at least one of: bringing EEGrhythms within a frequency band or bands from the first brain region andthe second brain region to no more than 30 degrees out of phase betweenthe average of said frequency band or bands from said brain regions;bringing extrema of frequency components of the first electricalactivity and the second electrical activity to no more than 30 degreesout of phase; or bringing zero crossings of frequency components of thefirst electrical activity and the second electrical activity to no morethan 30 degrees out of phase.
 24. A non-transitive, computer-readablestorage device for storing instructions that, when executed by aprocessor, perform a method, comprising: detecting a first electricalactivity relating to a first epileptic activity in at least a firstbrain sub-region of a patient; detecting a second electrical activityrelating to a second epileptic activity in at least a second brainsub-region of said patient; determining a phase-locking index between atleast said first electrical activity and said second electricalactivity; applying at least one first electrical stimulation to at leastone neural target of said patient to modify said phase-locking index ifsaid phase-locking index is outside a first range; and applying at leastone second electrical stimulation to at least one neural target of saidpatient to treat said epileptic activity.
 25. The non-transitive,computer-readable storage device of claim 24, wherein said first brainsub-region and said second sub-brain region are physically contiguous,physically adjacent, physically non-adjacent, anatomically connected,electrically connected, or two or more thereof.
 26. A medical devicesystem, comprising: an epileptic event detection module configured todetect an epileptic event; at least one sensor configured to collect oneor more electrical activity signals from at least one region of thebrain of a patient; a regularization determination module configured todetermine the regularity of said electrical activity, a neuronalregularization module configured to modify a regularity index ofelectrical activity in said at least one brain region of said patient; aphase-locking determination module configured to determine the degree ofphase-locking between said first electrical activity and said secondelectrical activity, a phase-locking module configured to modify aphase-locking index between a first electrical activity in said at leastone brain region and a second electrical activity in a second brainregion of said patient, and a stimulation module configured to apply anelectrical stimulation to at least one neural target of said patientbased on an indication of said epileptic event.